Integration of genetic, transcriptomic, and clinical data provides insight into 16p11.2 and 22q11

Integration of genetic, transcriptomic, and clinical data provides insight into 16p11.2 and 22q11

Publication date: Jun 23, 2020

Deletions and duplications of the 16p11.2 and 22q11.2 copy number variant (CNV) regions are associated with brain-related disorders including autism spectrum disorder, schizophrenia, bipolar disorder, obesity, and intellectual disability. The contribution of individual genes in each CNV to each phenotype is unknown. We propose a novel in silico approach to systematically interrogate each gene’s effect on brain-related disorders. As CNVs affect RNA copy number, we attempted to fine-map each CNV region by asking whether natural gene expression variation in any individual gene would increase risk for the same disorder(s). We first used large genotyped cohorts for five CNV-associated traits: autism spectrum disorder, schizophrenia, bipolar disorder, BMI, and IQ. Imputing the transcriptome from the genome, we performed association testing for CNV genes with the genotype datasets. We found individual genes within 16p11.2 associated with schizophrenia (TMEM219, INO80E, YPEL3), BMI (TMEM219, SPN, TAOK2,INO80E), and IQ (SPN), with independent replication. Using a conditional analysis, we showed that INO80E explains the schizophrenia association. Second, we used a biobank containing electronic health data and genotypes for 23,000 individuals to perform phenome-wide association studies with predicted expressions of 16p11.2 and 22q11.2 genes and over 1,500 health traits, finding eight significant gene-trait pairs. Third, we compared the medical phenome of CNV carriers to controls within an independent group of 3 million individuals. We identified CNV traits may have indicated genetic testing, other traits previously observed in CNV carriers, and novel traits. Our results provide new insight into the contribution of individual CNV genes to CNV-associated traits.


Concepts Keywords
Autism Duplication carrier status
Autism Spectrum Disorder Pacemaker device
Biobank Internal device
Bipolar Disorder Organisms Hallucinations
BMI Disorders TXNRD2 22q11
Body Mass Del CCDC116 Disorders
Brain SLC25A1 disorders
California Iron deficiency anemia
Cardiovascular GDPD3 Somatoform disorder
Conditional Amnestic cognitive disorders
Copy Number Angiodysplasia
Cytogenetic 5×10 alkalosis
Developmental Delay TRMT2A Psychogenic disorder
Drosophila DGCR8 Psychogenic disorder
ELN 2×10 cardiomegaly
Gene RTN4R Allergy
Genetic Immunity deficiency disorders
Genetic Polymorphisms Humoral dysfunction
Genetic Testing Negative BMI obesity
Genome Brain related disorders
Genotype PPIL2 disorders
Genotypes Del PPIL2 Nausea
Hallucinations DGCR2 disorders
Heritability Concerns epilepsy
Heterozygous PRRT2 Dementia
Homologs Peripheral vascular diseases
Intellectual Disability Related COMT Pericarditis
IQ Poisoning allergy
Loci CNV disorders
Locus 8×10 mental retardation
Mendelian Del MED15 Convulsions
Mutation Hyperpotassemia
MVP Del THAP7 Nausea
Nashville Factor disorder
Nervous System Del SLC25A1 Disorders
Obese SLC7A4 Disorders
Obesity MVP Heart failure
Outflow Neuromuscular disorders
Pathogenicity HIC2 Diseases
Penetrant MED15 disorders
Pharmacogenomics Recurrent seizures convulsions
Phenotype PI4KAP2 disorders
Phenotypes 3×10 disorders
Phenotypic Del SEPT5 Endocarditis
Point Mutations Del DGCR6L Bacteremia
Polymorphisms INO80E driver schizophrenia
Quantitative Trait Loci DGCR9 disorders
Risk Factor HIC2 disorders
San Francisco Deletion carriers dysfunction
Schizophrenia Pervasive developmental disorders
Symptom Del CA15P1 Nausea
Syndrome Schizophrenia BMI
Targeted Treatments YPEL3 Cardiac arrest
Transcriptome TUBA8 Aphasia
Transcriptomic Duplications obese obesity
Ucsf Rates schizophrenia
Underweight Del PRODH Nausea
Vanderbilt P2RX6P Abnormal movement
Velocardiofacial Syndrome Conduct disorders
Williams Syndrome Common symptom schizophrenia
Zebrafish Duplications schizophrenia
PheWS YPEL3 Disorders
Del HIC2 diseases
Rates obesity
Del RANBP1 Hypotension
Bariatric surgery
Organ systems
Medical specialties
DiGeorge syndrome


Type Source Name
disease MESH autism spectrum disorder
disease MESH schizophrenia
disease MESH bipolar disorder
disease MESH obesity
disease MESH intellectual disability
disease MESH Autism
disease MESH risk factor
disease MESH velocardiofacial syndrome
disease MESH underweight
disease MESH 22q11.2 duplication
disease MESH syndrome
disease MESH abnormalities
disease MESH Williams syndrome
disease MESH point mutations
disease MESH Hallucinations
disease MESH diagnosis
disease MESH mild cognitive impairment
disease MESH phenotypic variation
disease MESH epilepsy
disease MESH congenital heart defects
disease MESH cardiomegaly
disease MESH heart septal defects
disease MESH hyperpotassemia
disease MESH alkalosis
disease MESH valvular heart disease
disease MESH varicose veins
disease MESH benign neoplasm
disease MESH angiodysplasia
disease MESH hemorrhage
disease MESH congenital
drug DRUGBANK Methionine
disease MESH genetic disorders
disease MESH mental disorders
disease MESH anxiety disorder
disease MESH cardiomyopathies
disease MESH Dementia
disease MESH Heart failure
disease MESH Substance addiction
disease MESH Hearing loss
disease MESH Cardiac arrest
disease MESH ventricular fibrillation
disease MESH movement disorders
disease MESH Osteoporosis
disease MESH Alcohol related disorders
disease MESH peripheral vascular diseases
disease MESH Somatoform disorder
disease MESH Arteritis
disease MESH Sleep apnea
disease MESH Pericarditis
disease MESH Delirium
disease MESH Aortic aneurysm
disease MESH Aphasia
disease MESH development
disease MESH Dysphagia
disease MESH complications
disease MESH Autoimmune hemolytic anemias
disease MESH Ascites
disease MESH hematoma
disease MESH Deep vein thrombosis
disease MESH Hammer toe
disease MESH hypotension
disease MESH allergy
disease MESH Endocarditis
disease MESH ectasia
disease MESH Renal failure
disease MESH Tension headache
disease MESH Conduct disorders
disease MESH Stricture
disease MESH Iron deficiency anemia
disease MESH premature beats
disease MESH edema
disease MESH parasitic diseases
disease MESH scoliosis
disease MESH Aneurysm
disease MESH Bacteremia
disease MESH Hypercalcemia
disease MESH CNS infection
disease MESH poliomyelitis
disease MESH Diverticulum
disease MESH seizures
disease MESH involuntary movements
disease MESH Osteoarthrosis
disease MESH visual
disease MESH bronchitis
disease MESH bronchiolitis
disease MESH Primary pulmonary hypertension
disease MESH Paralysis
disease MESH spasm
disease MESH Posttraumatic stress disorder
disease MESH Hypovolemia
disease MESH Septicemia
disease MESH Bacterial infection
disease MESH Vascular dementia
disease MESH Hyperparathyroidism
disease MESH Depression
disease MESH Dental caries
disease MESH Neural tube defects
disease MESH Pneumococcal pneumonia
disease MESH Otitis media
disease MESH Suicidal ideation
drug DRUGBANK Calcium
disease MESH mood disorders
disease MESH secondary parkinsonism
disease MESH cerebrospinal fluid rhinorrhea
disease MESH anoxic brain damage
disease MESH sclerosis
disease MESH brain death

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